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Remote Memory Consolidation Based on Activity, Connectivity and Stability; Contribution of Neurons and Astrocytes.

Periodic Reporting for period 2 - RECENT-TO-REMOTE (Remote Memory Consolidation Based on Activity, Connectivity and Stability; Contribution of Neurons and Astrocytes.)

Reporting period: 2020-05-01 to 2021-10-31

"We are nothing more than the sum of our memories"(Michael Scott). Our remote memories, weeks to decades long, define who we are and how we experience the world, hence remote memory impairments have devastating consequences. Only a minority of recent memories (minutes to days long) will undergo a transition to remote memory, and those are usually the ones most important to the organism, as the longevity of a memory is tightly connected to its significance. Despite that, the vast majority of research was dedicated to recent memory, leaving the most basic questions unanswered: how and when are remote memories selected? How are they physically different from recent ones? What processes mediate the transition from recent to remote memory?

This project aims to address these questions, under the novel hypothesis that hippocampal neurons prioritized for remote consolidation are more likely to be connected to the anterior cingulate cortex (ACC), which in turn will be recruited for the long-term storage of memory. I further suggest a mechanistic investigation of the fundamental theoretical framework of 'systems consolidation' describing the transition from recent to remote memory, hypothesizing it is implemented by continuous interactions between brain regions, e.g. the hippocampus and the ACC. Finally, I propose a novel function for hippocampal astrocytes in recent and remote memory, ensemble allocation, and possibly in the independent representation of memory features. We are testing these hypotheses in a comprehensive by combining complementary conceptual and technical approaches.
In this time, we have established the experimental systems essential for implementation of the project, and made significant progress in all 3 objectives outlined in the grant proposal. Two streams of investigation had already matured into papers: a first major publication (Kol et al, Nature Neuroscience, In-Press), and another paper currently under review at Neuron. The major efforts and accomplishments are the following:
A. The parts of the project investigating the role of astrocytes in projection-specific effects on memory acquisition (Aim 3A, 3B) and the role of the CA1 and ACC projection in remote memory acquisition (Aim 2B, 2C) were completed, and the paper describing the findings was accepted for publication at Nature Neuroscience.
B. The part of the project investigating the role of astrocytes in ensemble selection based on cFos (part Aim of 3A) expression was finished, without any exciting findings on this specific question. We will continue investigating this question using tools with finer temporal resolution (see section D below). Nevertheless, this project required us to create an elaborate map of the mutual anatomy of astrocytes and neurons in the hippocampus, and a manuscript describing these findings is currently under review at Neuron.
C. We have imaged astrocytic activity in mice navigating a virtual environment (Aim 3C), and made very exciting discoveries: whereas single astrocytes do not encode specific locations (as opposed to neurons), it is possible to design an encoder that will infer the location of the mouse based on the activity of the astrocytic population. Furthermore, there is a clear difference in astrocytic activity when mice are navigating a familiar or a novel environment. A manuscript describing the results of these experiments is now in writing.
D. Our 2-photon microscope was upgraded (by ERC funding) to allow parallel 2-channel imaging of astrocytes and neurons. We are now calibrating co-expression of indicators in these two populations.
We are now running additional experiments to further decipher the involvement of astrocytes in encoding distinct environments across time. Imaging the same population of astrocytes in different spatial contexts can reveal whether these cells selectively encode each environment. Chronic imaging of astrocytes when the mouse is navigating in the same space on sequential days will help unveil remapping schemes.

Investigation of the interactions between neurons and astrocytes, using simultaneous imaging in behaving animals, will deepen our understanding of their unique involvement during cognitive tasks. We will track the activity of neurons and nearby astrocytes and test the correlations between their temporal activity patterns, and how it relates to external features of the environment and various aspects of behaviour.
Astrocytes in cleared mouse brain- aim 3A
Gi activation in Ca1 astrocytes prevents recruitment of CA 1 neurons projecting to ACC- aim 3A+3B
map of the mutual anatomy of astrocytes and neurons in the hippocampus- aim 3A
Inhabition of Ca1 neurons impairs acquisition of remote memory- aim 2B+2C